Platelet-derived growth factor (PDGF) is a disulfide-linked dimer consisting of two related polypeptide chains, designated PDGF-A and PDGF- B, that are the products of distinct genes. The gene encoding the human PDGF-B chain is the normal counterpart of the v-sis oncogene. Intervention with ligand-receptor interaction is a potential strategy for blocking PDGF related neoplastic processes. The ligand binding domains of the a and b PDGFRs were elucidated using a novel chimeric Ig fusion protein system. It was shown that high affinity PDGF-BB binding sites resided within receptor Ig-like domains 1 to 3. Additionally, b PDGFR-Ig fusion proteins were utilized to establish an ELISA-like assay format for identification of competitive antagonists that are capable of blocking PDGF-mediated responses. Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell growth and fibroblast growth factor (FGF) family member. The close relationship among different FGFRs has greatly increased the difficulty in generating specific immunochemical probes for study of KGFR biologic function. As an alternative strategy, a fusion protein was constructed comprising KGF and an IgG1 Fc domain (KGF-HFc) specific for detection of the KGFR. Ligand-mediated histochemical analysis of normal skin demonstrated the specific localization of KGFRs within the spinous layer, a zone of epithelial cell differentiation. In striking contrast, squamous cell carcinomas of skin lacked detectable KGFRs. Loss of tumor differentiation correlated with the loss of KGFR staining. Our present findings suggest that growth factor-Ig fusion proteins may be generally applicable for detection of growth factor receptors as well as diagnosis and prognosis of growth factor mediated malignancies.